Crystal Structure of the 11-cis Isomer of Pharaonis Halorhodopsin: Structural Constraints on Interconversions among Different Isomeric States.
Like other microbial rhodopsins, the light driven chloride pump halorhodopsin from Natronomonas pharaonis (pHR) contains a mixture of all-trans/15-anti and 13-cis/15-syn isomers in the dark adapted state. A recent crystallographic study of the reaction states of pHR has shown that reaction states with 13-cis/15-syn retinal occur in the anion pumping cycle that is initiated by excitation of the all-trans isomer. In this study, we investigated interconversions among different isomeric states of pHR in the absence of chloride ions. The illumination of chloride free pHR with red light caused a large blue shift in the absorption maximum of the retinal visible band. During this "red adaptation", the content of the 11-cis isomer increased significantly, while the molar ratio of the 13-cis isomer to the all-trans isomer remained unchanged. The results suggest that the thermally activated interconversion between the 13-cis and the all-trans isomers is very rapid. Diffraction data from red adapted crystals showed that accommodation of the retinal chromophore with the 11-cis/15-syn configuration was achieved without a large change in the retinal binding pocket. The measurement of absorption kinetics under illumination showed that the 11-cis isomer, with a λmax at 565 nm, was generated upon excitation of a red-shifted species (λmax = 625 nm) that was present as a minor component in the dark adapted state. It is possible that this red-shifted species mimics an O-like reaction state with 13-cis/15-syn retinal, which was hypothesized to occur at a late stage of the anion pumping cycle.


Origins of depression in later life.
Despite the burden of depression in late life, its origins present a paradox to investigators and clinicians alike. We review biological (genetics and heredity factors, neurotransmitter dysfunction, endocrine changes, vascular disorders, and medical co-morbidities), psychological (personality attributes, neuroticism, cognitive distortions, and the lack of emotional control and self-efficacy) and social (stressful life events, bereavement, chronic stress or strain, socio-economic disadvantage and impaired social support) origins of late-life depression based upon an extensive though not exhaustive review of the extant literature. In addition, modifying psychological and social factors are discussed. Older adults appear to be at greater risk for major depression biologically, such as depression resulting from vascular changes, yet the frequency of depression is lower compared to younger adults. Older adults may be protected psychologically due to factors such as socio-emotional selectivity and wisdom, compared to younger adults, and perhaps relatively protected from social risks. A biopsychosocial approach to evaluating the origins of late-life depression is heuristically valuable, a continual reminder of the many factors that contribute to the onset and persistence of clinically significant symptoms in late life.


Urinary tract stones: types, nursing care and treatment options.
Stones (calculi) in the urinary tract (urolithiasis) or kidney (nephrolithiasis) occur in 5% of the population. The lifetime risk of passing a stone is 8-10%. Men are twice as likely to develop stones, with the first episode occurring before 30 years of age. Stones are caused by the aggregation of crystalline mineral deposits in the urine. Calcium stones are the most common type of stone. Investigations for stone disease include plain X-ray, X-ray with contrast media, ultrasound imaging, and computed tomographic (CT) scanning. Treatment of stones is dependent on the size and location, e.g. lithotripsy is used to break down stones in the ureter or kidney, whereas litholapaxy is used for stones in the bladder that are too large to be passed urethrally. Alpha-blocker medication (e.g. tamsulosin) can facilitate spontaneous passing of a stone. Nurses have a crucial role in assessment, management and provision of discharge advice for patients. Strategies for preventing stones include increasing the urine output (by giving 2-3 litres of fluid per day) and dietary modification, particularly reduction in animal protein and salt content.


Acanthosis nigricans in type 2 diabetes: prevalence, correlates and potential as a simple clinical screening tool - a cross-sectional study in the Caribbean.
This study aimed to evaluate the role of acanthosis nigricans (AN) as a marker of Type 2 Diabetes Mellitus (T2DM) by studying its prevalence and relationship with age, ethnicity, anthropometry and other risk factors for T2DM in the Trinidadian population. 311 successive adult patients with T2DM were recruited at diabetic clinics and inpatient wards across Trinidad. The presence, severity and texture of AN at the neck were assessed. Demographic, clinical and anthropometric characteristics were also measured, and logistic regression was used to model their relationship with presence of AN. The mean (SD) age was 58.1 years (12.6). 55.6% were female. 61.1% were East Indian, 24.4% African and 14.5% mixed ethnicity. The mean (SD) BMI was 27.3 kg/m(2) (6.0) and the mean (SD) waist circumference was 96.7 cm (14.2). Prevalence of AN was 52.7% (95% CI 47.2, 58.3). THERE WAS A GREATER ODDS OF AN AMONG DIABETIC PATIENTS WHO WERE: younger (p < 0.001); female (OR 1.67; 95% CI 1.06, 2.62); or East Indian rather than African (0.45; 0.26, 0.77) or mixed (0.43; 0.22, 0.84) descendents. There was a greater age-, sex- and ethnicity-adjusted odds of AN among those: overweight (3.98; 2.10, 7.55) or obese (8.31; 3.84, 18.00) versus normal BMI; centrally obese (4.72; 2.65, 8.43); with history of hypertension (2.19; 1.27, 3.79) or history of hypercholesterolemia (1.72; 1.02, 2.90), but there was no evidence of this demographic-adjusted association (p > 0.4) between AN and history of previous MI or CVA, family history of T2DM, T2DM treatment regimen, duration of T2DM or random blood glucose. On further multivariable analysis, only age, sex, ethnicity, BMI and waist circumference were independently associated with AN (p < 0.05) and the effect of BMI varied with ethnicity. There was a high prevalence of AN both overall and across age, sex and ethnic groups of diabetic patients. AN exhibited much potential as a valuable addition to T2DM risk assessment in the Trinidadian and similar settings.


Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models.
Experimental evidence has directly implicated matrix metalloproteinases (MMPs) in the remodeling of the stromal tissue surrounding tumors. Thus, MMP inhibitors could limit the expansion of both neoplastic cell compartment and endothelial cell compartment of a tumor. Much of the work on the role of MMP inhibitors has concentrated on their inhibitory effects on tumor cell invasion. We have examined the effects of a new MMP inhibitor, KB-R7785 (acting on MMP-1, MMP-3, and MMP-9), on tumor angiogenesis and metastasis of murine colon adenocarcinoma (C-26) in two tumor models in BALB/c mice (transparent chamber model and lung colonization model). KB-R7785 has not shown inhibitory effects on in vitro growth of either C-26 or KOP2.16 murine endothelial cells. In vivo, KB-R7785 administrated twice daily for 15 days (100 mg/kg, i.p.), starting the day of tumor inoculation (5 x 10(5) C26 cells) in transparent chamber, has resulted in 88.2% suppression of tumor growth, compared with that in vehicle-administered mice (controls). Tumors grown in controls have doubled their area in 3.3 days, whereas those treated by KB-R7785 progressed almost four times slower (tumor area doubling time, 12 days). KB-R7785 rendered centrally avascular tumors with only a rim of peripheral neovasculature, which had significant lower functional vascular density and vascular area than the corresponding parameters in control tumors 10 days after inoculation [79.9+/-6.7 cm/cm2 versus 164.1+/-10.1 cm/cm2 (P < 0.01) and 19.8+/-1.5% versus 42.6+/-2.7% (P < 0.01), respectively]. In the lung colonization model (tail vein inoculation of 5 x 10(5) C-26 cells), administration of KB-R7785 (100 mg/kg, i.p.) twice daily for 20 days has reduced the number of surface metastasis by 85.8% and abolished the tumor burden, as compared with controls. The few metastatic colonies found in the lungs of KB-R7785 treated mice appeared to be dormant (i.e., staining with von Willebrand factor antibody revealed few, if any, positive cells within the metastatic foci from MMP inhibitor-treated lungs, whereas terminal deoxynucleotidyl transferase-mediated nick end labeling showed a 4-fold increase in the rate of tumor cell apoptosis compared with controls. The fact that KB-R7785 interferes with early steps of angiogenesis and cancer spread suggests that MMP inhibitors may control both primary and secondary tumor growths by limiting the expansion of endothelial cells, as well as cancer cells, composing the tumors.


Neck pain intensity does not predict pressure pain hyperalgesia: re-analysis of seven randomized controlled trials.
To determine factors, including pain intensity, associated with pressure pain sensitivity in chronic non-specific neck pain and with changes after therapeutic interventions. This re-analysis used pooled data from 7 randomized controlled clinical trials. Pressure pain thresholds were assessed at the hand and at the site of maximal pain in the neck region before and after different non-pharmacological interventions. Age, gender, neck pain intensity and duration, mental health, expectancy and time interval between measurements were used to determine factors influencing pressure pain thresholds as well as pressure pain threshold changes. A total of 346 patients (77 males, 269 females, mean age 52.6 years (standard deviation 12.0 years)) were included in study, 306 of whom provided a complete data-set for analysis. Pressure pain thresholds at the neck area or the hand did not correlate with pain intensity. Changes in pressure pain thresholds correlated with time between measurements, indicating time-sensitive changes. No coherent correlations between pressure pain thresholds and pain intensity were found. Further research is needed to evaluate the relationship between pain intensity and pressure pain thresholds before its use as a valid substitute of pain rating can be supported. Until then, the results of trials with respect to using pressure pain thresholds as an outcome variable must be interpreted with care.


Cytomegalovirus infection masquerading as carcinoma in a lung transplant patient.
In lung transplant patients, most infections produce radiographically diffuse or lobar infiltrates. Solitary nodules suggesting neoplasm may arise in lung transplant patients with lung infections. We describe a 45-year-old woman who underwent bilateral lung transplantation to treat bilateral bronchiectasis and lung fibrosis resulting from Hodgkin disease. Five months later, a solitary mass was identified on chest radiograph in the left upper lobe and left superior mediastinum. Low-power examination of wedge biopsies of the mass showed a florid proliferation of cells with clear to bubbly to eosinophilic cytoplasm and moderate nuclear atypia, proliferating fibroblasts, and necrosis, suggesting a clear cell carcinoma (possibly metastatic renal cell carcinoma). Intranuclear inclusions compatible with cytomegalovirus were identified on high-power examination and confirmed by immunohistochemistry. In lung transplant patients, a cytomegalovirus infection may mimic malignancy both radiographically and on initial histopathologic examination.


Intercellular transfer of transferrin receptor by a contact-, Rab8-dependent mechanism involving tunneling nanotubes.
Intercellular communication between cancer cells, especially between cancer and stromal cells, plays an important role in disease progression. We examined the intercellular transfer of organelles and proteins in vitro and in vivo and the role of tunneling nanotubes (TNTs) in this process. TNTs are membrane bridges that facilitate intercellular transfer of organelles of unclear origin. Using 3-dimensional quantitative and qualitative confocal microscopy, we showed that TNTs contain green fluorescent protein (GFP)-early endosome antigen (EEA) 1, GFP Rab5, GFP Rab11, GFP Rab8, transferrin (Tf), and Tf receptor (Tf-R) fused to mCherry (Tf-RmCherry). Tf-RmCherry was transferred between cancer cells by a contact-dependent but secretion-independent mechanism. Live cell imaging showed TNT formation preceding the transfer of Tf-RmCherry and involving the function of the small guanosine triphosphatase (GTPase) Rab8, which colocalized with Tf-RmCherry in the TNTs and was cotransferred to acceptor cells. Tf-RmCherry was transferred from cancer cells to fibroblasts, a noteworthy finding that suggests that this process occurs between tumor and stromal cells in vivo. We strengthened this hypothesis in a xenograft model of breast cancer using enhanced (e)GFP-expressing mice. Tf-RmCherry transferred from tumor to stromal cells and this process correlated with an increased opposite transfer of eGFP from stromal to tumor cells, together pointing toward complex intercellular communication at the tumor site.


Computational fluid dynamics of cerebral aneurysm coiling using high-resolution and high-energy synchrotron X-ray microtomography: comparison with the homogeneous porous medium approach.
Computational modeling of intracranial aneurysms provides insights into the influence of hemodynamics on aneurysm growth, rupture, and treatment outcome. Standard modeling of coiled aneurysms simplifies the complex geometry of the coil mass into a homogeneous porous medium that fills the aneurysmal sac. We compare hemodynamics of coiled aneurysms modeled from high-resolution imaging with those from the same aneurysms modeled following the standard technique, in an effort to characterize sources of error from the simplified model. Physical models of two unruptured aneurysms were created using three-dimensional printing. The models were treated with coil embolization using the same coils as those used in actual patient treatment and then scanned by synchrotron X-ray microtomography to obtain high-resolution imaging of the coil mass. Computational modeling of each aneurysm was performed using patient-specific boundary conditions. The coils were modeled using the simplified porous medium or by incorporating the X-ray imaged coil surface, and the differences in hemodynamic variables were assessed. X-ray microtomographic imaging of coils and incorporation into computational models were successful for both aneurysms. Porous medium calculations of coiled aneurysm hemodynamics overestimated intra-aneurysmal flow, underestimated oscillatory shear index and viscous dissipation, and over- or underpredicted wall shear stress (WSS) and WSS gradient compared with X-ray-based coiled computational fluid dynamics models. Computational modeling of coiled intracranial aneurysms using the porous medium approach may inaccurately estimate key hemodynamic variables compared with models incorporating high-resolution synchrotron X-ray microtomographic imaging of complex aneurysm coil geometry.


Genome sequence of the plant pathogen and biotechnology agent Agrobacterium tumefaciens C58.
Agrobacterium tumefaciens is a plant pathogen capable of transferring a defined segment of DNA to a host plant, generating a gall tumor. Replacing the transferred tumor-inducing genes with exogenous DNA allows the introduction of any desired gene into the plant. Thus, A. tumefaciens has been critical for the development of modern plant genetics and agricultural biotechnology. Here we describe the genome of A. tumefaciens strain C58, which has an unusual structure consisting of one circular and one linear chromosome. We discuss genome architecture and evolution and additional genes potentially involved in virulence and metabolic parasitism of host plants.


Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults.
The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa flavanol-containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.


System justification and the defense of committed relationship ideology.
A consequential ideology in Western society is the uncontested belief that a committed relationship is the most important adult relationship and that almost all people want to marry or seriously couple (DePaulo & Morris, 2005). In the present article, we investigated the extent to which the system justification motive may contribute to the adoption of this ideology. In Studies 1 and 2, we examined whether a heightened motive to maintain the status quo would increase defense of committed relationship values. In Study 3, we examined the reverse association, that is, whether a threat to committed relationship ideology would also affect sociopolitical system endorsement. As past research has found that the justification of political systems depends upon how much these systems are perceived as controlling, in Study 4 we tested whether the defense of the system of committed relationships would also increase when framed as controlling. Results from Studies 1-4 were consistent with our hypotheses, but only for men. In Study 5, using cross-cultural data, we sought to replicate these findings correlationally and probe for a cause of the gender effect. Results from more than 33,000 respondents indicated a relationship (for men) between defense of the sociopolitical system and defense of marriage in countries where the traditional advantages of men over women were most threatened. In Studies 6 and 7, we investigated when this gender difference disappears. Results revealed that when we measured (Study 6) or manipulated (Study 7) personal relationship identity rather than relationship ideology, effects also emerge for women.


Effect of cryotherapy on dose of adjuvant paclitaxel in early-stage breast cancer.
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel. Though no pharmacological agents have been identified to prevent CIPN, cryotherapy with frozen gloves and socks may reduce the risk of developing CIPN and thereby increase the likelihood of patients completing the planned dose of paclitaxel. Among women with early-stage breast cancer who received at least one cycle of paclitaxel, 119 were included in the 2016 cohort who received cryotherapy when they developed symptoms of CIPN, and 96 patients in the 2017 cohort who received prophylactic cryotherapy. From electronic patient records, data were abstracted on dates and doses of adjuvant paclitaxel, dose reductions, cycle delays, symptoms of CIPN, and whether and when frozen gloves and socks were used. The outcome was the proportion of patients completing the planned 720 mg/m2 of paclitaxel cumulated over nine cycles. The hazard ratio (HR) of a dose-limiting event due to CIPN was estimated in a Cox proportional hazards model. In the 2016 cohort, cryotherapy was needed due to symptoms of CIPN in 54 (45%) patients. Significantly, more patients, 77% in the 2017 cohort, completed the planned dose of 720 mg/m² compared with 64% in the 2016 cohort, p = 0.017. The HR of a dose reduction or cessation due to CIPN, adjusted for age and HER-2 status, was 0.50 (95% confidence interval 0.30-0.84), p = 0.009, for the 2017 cohort compared with the 2016 cohort. The results of this study suggest that prophylactic cryotherapy may reduce the risk of a dose-limiting event due to CIPN and increase the proportion of patients completing the planned dose of paclitaxel in adjuvant treatment of early-stage breast cancer. Despite this, CIPN remains to be an important dose-limiting toxicity of paclitaxel.


Mechanically rigid supramolecular assemblies formed from an Fmoc-guanine conjugated peptide nucleic acid.
The variety and complexity of DNA-based structures make them attractive candidates for nanotechnology, yet insufficient stability and mechanical rigidity, compared to polyamide-based molecules, limit their application. Here, we combine the advantages of polyamide materials and the structural patterns inspired by nucleic-acids to generate a mechanically rigid fluorenylmethyloxycarbonyl (Fmoc)-guanine peptide nucleic acid (PNA) conjugate with diverse morphology and photoluminescent properties. The assembly possesses a unique atomic structure, with each guanine head of one molecule hydrogen bonded to the Fmoc carbonyl tail of another molecule, generating a non-planar cyclic quartet arrangement. This structure exhibits an average stiffness of 69.6 ± 6.8 N m-1 and Young's modulus of 17.8 ± 2.5 GPa, higher than any previously reported nucleic acid derived structure. This data suggests that the unique cation-free "basket" formed by the Fmoc-G-PNA conjugate can serve as an attractive component for the design of new materials based on PNA self-assembly for nanotechnology applications.


Long-term changes in graft height after maxillary sinus augmentation, onlay bone grafting, and combination of both techniques: a long-term retrospective cohort study.
This investigation focused on long-term changes in graft height, implant survival rate, and peri-implant tissue conditions of dental implants placed in alveolar ridges after augmentation procedures with a follow-up of 10 years. We conducted a retrospective cohort study with prospective long-term follow-up of 25 patients with edentulous severe atrophic maxillary situations who received a vertical augmentation procedure with autologous bone prior to implant placement. The participants were divided into three groups according to whether they underwent sinus elevation, onlay grafting, or a combination of both techniques. After a four-month healing period, 127 implants were inserted in the corresponding regions. Following a six-month healing period, the participants underwent prosthodontic rehabilitation, incorporating a fixed or removable implant denture. The cohort was clinically and radiographically followed up 1, 5, and 10 years after augmentation. The following parameters were measured: radiographic vertical bone changes, implant loss, peri-implant pocket depth (PD), width of keratinized mucosa (KM), sulcus fluid flow rate (SFFR), and the radiographic distance between the implant shoulder and the first visible bone-to-implant contact (DIB). Seven implants were lost during the observation period, resulting in a cumulative 10-year survival rate of 94.48%. Significant bone loss occurred during the first 12 months, after which the resorption slowed down and bone height eventually stabilized. After 10 years, the total vertical bone loss was 27.51% after onlay grafting, 28.14% after sinus elevation, and 30.24% in the combination group, with no statistically significant between-group differences. Peri-implant follow-up examinations revealed a positive correlation between SFFR and PD, respectively, DIB, and a negative correlation between SFFR and KM. The treatment method does not seem to impact vertical bone loss following augmentation using autologous grafts. This approach results in long-term stability of dental implants. A sufficient width of keratinized peri-implant mucosa is important to prevent peri-implant bone loss and inflammation.


Collaborative development and implementation of a knowledge brokering program to promote research use in Burkina Faso, West Africa.
Despite efforts expended over recent decades, there is a persistent gap between the production of scientific evidence and its use. This is mainly due to the difficulty of bringing such knowledge to health workers and decision-makers so that it can inform practices and decisions on a timely basis. One strategy for transferring knowledge to potential users, that is, gaining increasing legitimacy, is knowledge brokering (KB), effectiveness of which in certain conditions has been demonstrated through empirical research. However, little is known about how to implement such a strategy, especially in the African context. The KB program presented here is aimed specifically at narrowing the gap by making scientific knowledge available to users with the potential to improve health-related practices and decision making in Burkina Faso. The program involves Canadian and African researchers, a knowledge broker, health practitioners, and policy-makers. This article presents the collaborative development of the KB strategy and the evaluation of its implementation at year 1. The KB strategy was developed in stages, beginning with a scoping study to ensure the most recent studies were considered. Two one-day workshops were then conducted to explore the problem of low research use and to adapt the strategy to the Burkinabè context. Based on these workshops, the KB program was developed and brokers were recruited and trained. Evaluation of the program's implementation after the first year showed that: 1) the preparatory activities were greatly appreciated by participants, and most considered the content useful for their work; 2) the broker had carried out his role in accordance with the logic model; and 3) this role was seen as important by the participants targeted by the activities and outputs. Participants made suggestions for program improvements in subsequent years, stressing particularly the need to involve decision-makers at the central level.


Antifungal susceptibility, genotyping, resistance mechanism, and clinical profile of Candida tropicalis blood isolates.
Candida tropicalis is one of the major candidaemia agents, associated with the highest mortality rates among Candida species, and developing resistance to azoles. Little is known about the molecular mechanisms of azole resistance, genotypic diversity, and the clinical background of C. tropicalis infections. Consequently, this study was designed to address those questions. Sixty-four C. tropicalis bloodstream isolates from 62 patients from three cities in Iran (2014-2019) were analyzed. Strain identification, antifungal susceptibility testing, and genotypic diversity analysis were performed by MALDI-TOF MS, CLSI-M27 A3/S4 protocol, and amplified fragment length polymorphism (AFLP) fingerprinting, respectively. Genes related to drug resistance (ERG11, MRR1, TAC1, UPC2, and FKS1 hotspot9s) were sequenced. The overall mortality rate was 59.6% (37/62). Strains were resistant to micafungin [minimum inhibitory concentration (MIC) ≥1 μg/ml, 2/64], itraconazole (MIC > 0.5 μg/ml, 2/64), fluconazole (FLZ; MIC ≥ 8 μg/ml, 4/64), and voriconazole (MIC ≥ 1 μg/ml, 7/64). Pan-azole and FLZ + VRZ resistance were observed in one and two isolates, respectively, while none of the patients were exposed to azoles. MRR1 (T255P, 647S), TAC1 (N164I, R47Q), and UPC2 (T241A, Q340H, T381S) mutations were exclusively identified in FLZ-resistant isolates. AFLP fingerprinting revealed five major and seven minor genotypes; genotype G4 was predominant in all centers. The increasing number of FLZ-R C. tropicalis blood isolates and acquiring FLZ-R in FLZ-naive patients limit the efficiency of FLZ, especially in developing countries. The high mortality rate warrants reaching a consensus regarding the nosocomial mode of C. tropicalis transmission.


Can childcare work be designed to promote moderate and vigorous physical activity, cardiorespiratory fitness and health? Study protocol for the Goldilocks-childcare randomised controlled trial.
Despite extensive efforts, issues like obesity and poor physical capacity remain challenges for a healthy work life in several occupations. The Goldilocks work principle offers a new approach, encouraging design of productive work to promote physical capacity and health. This paper presents the protocol for the Goldilocks-childcare study, a randomised controlled intervention trial aiming to evaluate the effectiveness of implementing the Goldilocks work principle in childcare. The primary aim of the intervention is to increase time in moderate to vigorous physical activity (MVPA) by having the childcare workers act as active role models for children in daily playful physical activities, and thereby improve cardiorespiratory fitness and health of the workers. The study is a cluster-randomised trial with a usual-practice wait-list control group. The 10-week intervention consists of two phases. In the first, the childcare workers will participate in two participatory workshops aiming to a) develop playful physical activities ('Goldilocks-games') for children in which childcare workers participate as active role models at MVPA intensity, and b) develop action plans for implementation of the Goldilocks-games in daily work routines. In the second phase, childcare institutions will implement the Goldilocks-games. The primary outcome is working time spent in MVPA, and secondary outcomes are cardiorespiratory fitness, sleeping heart rate, perceived need for recovery, and productivity. Primary outcome and process evaluation will be based on direct measurements of physical activity and heart rate, determination of cardiorespiratory fitness, and questionnaires. If proven effective, the Goldilocks work principle has a large potential for promoting sustainable health and working lives of childcare workers. ISRCTN, ISRCTN15644757, Registered 25th December 2019.


A Defect in Lipoprotein Modification by Lgt Leads to Abnormal Morphology and Cell Death in Escherichia coli That Is Independent of Major Lipoprotein Lpp.
Lgt is an essential enzyme in proteobacteria and therefore a potential target for novel antibiotics. The effect of Lgt depletion on growth, morphology, and viability was studied in Escherichia coli to assess whether absence of Lgt leads to cell death. Two Lgt depletion strains were used in which lgt was under the control of an arabinose-inducible promoter that allowed regulation of Lgt protein levels. Reduced levels of Lgt led to severe growth and morphological defects that could be restored by expressing lgt in trans, demonstrating that only Lgt is responsible for the distorted phenotypes. In the absence of major lipoprotein Lpp, growth defects were partially restored when low levels of Lgt were still present; however, lgt could not be deleted in the absence of Lpp. Our results demonstrate that Lpp is not the main cause of cell death under conditions of Lgt depletion and that other lipoproteins are important in cell envelope biogenesis and cell viability. Specific inhibitors of Lgt are thus promising for the development of novel antibiotics. IMPORTANCE Incomplete maturation and envelope mislocalization of lipoproteins, through inhibition or mutations in lipoprotein modification enzymes or transport to the outer membrane, are lethal in proteobacteria. Resistance to small-molecule inhibition or the appearance of suppressor mutations is often directly correlated with the presence of abundant outer membrane lipoprotein Lpp. Our results show that Lgt, the first enzyme of the lipoprotein modification pathway, is still required for growth and viability in the absence of Lpp and thus is necessary for the function of other essential lipoproteins in the cell envelope. This adds credence to the hypothesis that Lgt is essential in proteobacteria and an attractive target for the development of novel antibiotics.


Fatal Melioidosis in a Newborn from Hainan, China.
Herein, we report a case of fatal melioidosis in a newborn. The newborn died of serious melioidosis with respiratory and multiorgan failure at 16 days of age despite extensive treatment with antibiotics and methylprednisolone. Burkholderia pseudomallei was isolated from the infant's blood and cerebrospinal fluid and identified as a novel sequence type (ST-1341). His father had cough and fever when the newborn was born, and a localized patchy infiltration on the right upper lung was seen in chest radiography, but B. pseudomallei was not isolated. Two years later, the father developed cough and fever again, and the same novel sequence type of B. pseudomallei was isolated from the blood of the father. It is postulated that transmission of B. pseudomallei from the father to the newborn might have occurred during close contact in the first couple of days after birth. Given the high mortality of neonatal melioidosis, particular attention must be paid when the caretakers of the newborn develop fever of unknown origin in a melioidosis-endemic region.


Models of asthma: density-equalizing mapping and output benchmarking.
Despite the large amount of experimental studies already conducted on bronchial asthma, further insights into the molecular basics of the disease are required to establish new therapeutic approaches. As a basis for this research different animal models of asthma have been developed in the past years. However, precise bibliometric data on the use of different models do not exist so far. Therefore the present study was conducted to establish a data base of the existing experimental approaches. Density-equalizing algorithms were used and data was retrieved from a Thomson Institute for Scientific Information database. During the period from 1900 to 2006 a number of 3489 filed items were connected to animal models of asthma, the first being published in the year 1968. The studies were published by 52 countries with the US, Japan and the UK being the most productive suppliers, participating in 55.8% of all published items. Analyzing the average citation per item as an indicator for research quality Switzerland ranked first (30.54/item) and New Zealand ranked second for countries with more than 10 published studies. The 10 most productive journals included 4 with a main focus allergy and immunology and 4 with a main focus on the respiratory system. Two journals focussed on pharmacology or pharmacy. In all assigned subject categories examined for a relation to animal models of asthma, immunology ranked first. Assessing numbers of published items in relation to animal species it was found that mice were the preferred species followed by guinea pigs. In summary it can be concluded from density-equalizing calculations that the use of animal models of asthma is restricted to a relatively small number of countries. There are also differences in the use of species. These differences are based on variations in the research focus as assessed by subject category analysis.


Aluminum contamination of food during culinary preparation: Case study with aluminum foil and consumers' preferences.
The aim of the work was to estimate the degree of aluminum leakage from aluminum foil during baking process of selected food/meals. The experiment included 11 different types of food (Atlantic salmon Salmo salar, mackerel Scomber scombrus, duck breasts, cheese Hermelín, tomato, paprika, Carlsbad dumplings, pork roast, pork neck, chicken breasts, and chicken thighs) baked both marinated and not marinated. The aluminum content was measured by AAS and ICP/MS methods. The highest aluminum increase was observed in the samples of marinated Salmo salar (41.86 ± 0.56 mg/kg), Scomber scombrus (49.34 ± 0.44 mg/kg), and duck breast (117.26 ± 1.37 g/kg). The research was also supported by the survey that consisted of 784 respondents with different sociodemographic characteristics. The study clearly showed the occurrence of aluminum contamination of food when it is prepared by baking in aluminum foil. It cannot be concluded that aluminum leakage will occur with each type of food. The aluminum contents found among investigated samples are not alarming, though the increase was measured up to 40 times. On the other hand, revealed aluminum contents can represent a risk for younger/smaller children and for individuals with diagnosed certain ailments.


An investigation of the origin of extracellular GABA in rat nucleus accumbens measured in vivo by microdialysis.
GABA transmission in the nucleus accumbens is believed to play a central role in motivational processes and the expression of psychostimulant drug action. Here we report measurements of extracellular GABA in nucleus accumbens of the rat and investigate its origin. Extracellular GABA was detected using microdialysis in combination with a novel HPLC-based assay. In the awake rat, GABA in the microdialysates (1) increased 10-fold following perfusion with 0.5 mM nipecotic acid, a GABA releasing agent and uptake blocker, (2) increased 7-fold following local perfusion with 50 mM KCl, (3) decreased 50% following perfusion with tetrodotoxin, (4) decreased 50% following perfusion with a Ca(2+(-free medium and (5) decreased 40% following perfusion with high (12.5 mM) MgCl. Finally, in the anaesthetized rat, GABA in the microdialysates decreased 50% following i.p. injection of 100 mg/kg 3-mercaptoproprionic acid, a GABA synthesis inhibitor. We conclude that GABA in microdialysates from nucleus accumbens of the rat (awake) responds appropriately to selected pharmacological agents and derives at least in part (50%) from neurones.


Vascular function in adults with cyanotic congenital heart disease.
Patients with cyanotic congenital heart disease (CCHD) may have a low burden of atherosclerosis. Endothelial dysfunction is an early stage of atherosclerosis and endothelial function is previously studied in smaller CCHD groups with different techniques and variable results. We aimed to examine endothelial function and carotid atherosclerosis in a larger group of CCHD patients. This multicentre study assessed endothelial function in adults with CCHD and controls by measuring the dilatory response of the brachial artery to post-ischemic hyperaemia (endothelium-dependent flow-mediated-vasodilatation (FMD)), and to nitroglycerin (endothelium-independent nitroglycerin-induced dilatation (NID)). Flow was measured at baseline and after ischaemia (reactive hyperaemia). Carotid-intima-media-thickness (CIMT), prevalence of carotid plaque and plaque thickness (cPT-max) were evaluated ultrasonographically. Lipoproteins, inflammatory and vascular markers, including sphingosine-1-phosphate (S1P) were measured. Forty-five patients with CCHD (median age 50 years) and 45 matched controls (median age 52 years) were included. The patients presented with lower reactive hyperaemia (409 ± 114% vs. 611 ± 248%, p < 0.0001), however preserved FMD response compared to controls (106.5 ± 8.3% vs. 106.4 ± 6.1%, p = 0.95). In contrast, NID was lower in the patients (110.5 ± 6.1% vs. 115.1 ± 7.4%, p = 0.053). There was no difference in CIMT, carotid plaque or cPT-max. The patients presented with lower high-density-lipoprotein cholesterol, and higher level of inflammatory markers and S1P. Adults with CCHD had preserved FMD in the brachial artery, but impaired NID response and lower reactive hyperaemia than controls. The preserved FMD and the comparable prevalence of carotid atherosclerosis indicate that CCHD patients have the same risk of atherosclerosis as controls.


Absolute Bioavailability, Tissue Distribution, and Excretion of Erinacine S in Hericium erinaceus Mycelia.
Erinacine S, so far known to have been produced only in Hericium erinaceus mycelia, has just recently been discovered and is able to reduce amyloid plaque growth and improve neurogenesis in aged brain of rats. However, few investigations have been conducted on the absorption, distribution, and excretion study of Erinacine S. This study aimed to investigate the absolute bioavailability, tissue distribution, and excretion of Erinacine S in H. Erinaceus mycelia in eight-week old Sprague-Dawley rats. After oral administration and intravenous administration of 2.395 g/kg body weight of the H. erinaceus mycelia extract (equivalent to 50 mg/kg body weight Erinacine S) and 5 mg/kg of Erinacine S, respectively, the absolute bioavailability was estimated as 15.13%. In addition, Erinacine S was extensively distributed in organs such as brain, heart, lung, liver, kidney, stomach, small intestine, and large intestine. The maximum concentration of Erinacine S was observed in the stomach, 2 h after the oral administration of H. erinaceus mycelia extract, whereas the maximum amount of Erinacine S found in other tissues were seen after 8 h. Total amount of unconverted Erinacine S eliminated in feces and urine in 24 h was 0.1% of the oral dosage administrated. This study is the first to show that Erinacine S can penetrate the blood-brain barrier of rats and thus support the development of H. erinaceus mycelia, for the treatment of neurological diseases.


A systematic overview of measurement-based care in the treatment of childhood and adolescent depression.
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders affecting children and adolescents. The significant psychiatric, social, and functional impairments associated with this disorder coupled with the high incidence of relapse indicate a need for continued efforts to enhance treatment. Current empirically supported treatments for childhood and adolescent MDD include psychotropic medications, psychotherapy, and a combination of both treatments, with selection of the most appropriate strategy depending on symptom severity. One strategy to enhance treatment outcome is the use of measurement-based care. This article provides a systematic review of measurement-based care in the treatment of childhood and adolescent MDD. It also presents a comprehensive analysis of widely used depression rating scales and discusses their utility in clinical practice. This review found evidence supporting the utility and benefit of depression rating scales to document depression severity in children and adolescents. We also found evidence suggesting that many of these scales are time efficient, and that both clinician-rated and self-rated scales provide accurate assessment of depressive symptomatology. Future research is warranted to examine the utility of measurement-based care in clinical practice with child and adolescent populations.


Hard sphere-like glass transition in eye lens α-crystallin solutions.
We study the equilibrium liquid structure and dynamics of dilute and concentrated bovine eye lens α-crystallin solutions, using small-angle X-ray scattering, static and dynamic light scattering, viscometry, molecular dynamics simulations, and mode-coupling theory. We find that a polydisperse Percus-Yevick hard-sphere liquid-structure model accurately reproduces both static light scattering data and small-angle X-ray scattering liquid structure data from α-crystallin solutions over an extended range of protein concentrations up to 290 mg/mL or 49% vol fraction and up to ca. 330 mg/mL for static light scattering. The measured dynamic light scattering and viscosity properties are also consistent with those of hard-sphere colloids and show power laws characteristic of an approach toward a glass transition at α-crystallin volume fractions near 58%. Dynamic light scattering at a volume fraction beyond the glass transition indicates formation of an arrested state. We further perform event-driven molecular dynamics simulations of polydisperse hard-sphere systems and use mode-coupling theory to compare the measured dynamic power laws with those of hard-sphere models. The static and dynamic data, simulations, and analysis show that aqueous eye lens α-crystallin solutions exhibit a glass transition at high concentrations that is similar to those found in hard-sphere colloidal systems. The α-crystallin glass transition could have implications for the molecular basis of presbyopia and the kinetics of molecular change during cataractogenesis.


Stathmin/Op18 is a novel mediator of vinblastine activity.
Microtubule (MT) dynamic instability is tightly regulated by stabilizing and destabilizing proteins, the latter being exemplified by stathmin/Op18, a protein known to destabilize MTs. Studies in cells have indicated that the level of stathmin expression modifies the cytotoxicity of antimicrotubule drugs, such as vinblastine (VLB). Using isothermal titration calorimetry and analytical ultracentrifugation, we show that VLB increases the affinity of stathmin for tubulin 50-fold (and vice versa). These results are the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and reveal a new mechanism of action for VLB.


The course of PTSD, major depression, substance abuse, and somatization after a natural disaster.
Flood research has used a variety of methods, yielding inconsistent findings. Universal definitions of illness are paramount to the science of psychiatric epidemiology of disasters. St. Louis area survivors (N = 162) of the Great Midwestern Floods of 1993 received a structured diagnostic assessment at 4 and 16 months postdisaster, with 88% follow-up. The purpose of the assessment was to examine predisaster and postdisaster rates of disorders and symptoms. Flood-related posttraumatic stress disorder was diagnosed in 22% and 16% at index and follow-up, respectively. Comorbidity with major depression determined whether the posttraumatic stress disorder would have remitted by 1 year later. Nearly one half of the men in the sample had a pre-existing alcohol use disorder. Virtually no new substance abuse followed the floods, and hence, substance abuse did not develop in response to the disaster or as part of coping with its aftermath. Somatization disorder was not observed; new somatoform symptoms represented a fraction of postflood somatic complaints. Findings are inconsistent with causal attribution of floods in the etiology of alcohol abuse and somatization. Methodological differences may account for much of the apparent discrepancy of these findings, with recent reports of increased alcohol use and somatic symptoms observed after other disasters.


Adipose tissue, muscle, and function: potential mediators of associations between body weight and mortality in older adults with type 2 diabetes.
Studies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality. The AGES-Reykjavik cohort comprised participants aged 66-96 years with diabetes defined by fasting glucose, medications, or self-report. BMI was determined from measured height and weight and classified as normal (18.5-24.9 kg/m(2), n = 117), overweight (25.0-29.9 kg/m(2), n = 293, referent group) or obese (≥30.0 kg/m(2), n = 227). Thigh muscle area and intermuscular, visceral, and subcutaneous adipose tissues were assessed with computed tomography. Function was assessed from gait speed and knee extensor strength. Hazard ratios (HRs) and 95% CIs were estimated by Cox proportional hazards regression adjusted for demographics and diabetes-related risk factors. The median follow-up was 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12-2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87-2.11]) and gait speed (HR 1.44 [95% CI 0.91-2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality. Normal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size.


Binding leverage as a molecular basis for allosteric regulation.
Allosteric regulation involves conformational transitions or fluctuations between a few closely related states, caused by the binding of effector molecules. We introduce a quantity called binding leverage that measures the ability of a binding site to couple to the intrinsic motions of a protein. We use Monte Carlo simulations to generate potential binding sites and either normal modes or pairs of crystal structures to describe relevant motions. We analyze single catalytic domains and multimeric allosteric enzymes with complex regulation. For the majority of the analyzed proteins, we find that both catalytic and allosteric sites have high binding leverage. Furthermore, our analysis of the catabolite activator protein, which is allosteric without conformational change, shows that its regulation involves other types of motion than those modulated at sites with high binding leverage. Our results point to the importance of incorporating dynamic information when predicting functional sites. Because it is possible to calculate binding leverage from a single crystal structure it can be used for characterizing proteins of unknown function and predicting latent allosteric sites in any protein, with implications for drug design.


Readmissions From Venous Thromboembolism After Complex Cancer Surgery.
Venous thromboembolism (VTE) is a major cause of preventable morbidity and mortality after cancer surgery. Venous thromboembolism events that are significant enough to require hospital readmission are potentially life threatening, yet data regarding the frequency of these events beyond the 30-day postoperative period remain limited. To determine the rates, outcomes, and predictive factors of readmissions owing to VTE up to 180 days after complex cancer operations, using a national data set. A retrospective cohort study of the 2016 Nationwide Readmissions Database was performed to study adult patients readmitted with a primary VTE diagnosis. Data obtained from 197 510 visits for 126 104 patients were analyzed. This was a multicenter, population-based, nationally representative study of patients who underwent a complex cancer operation (defined as cystectomy, colectomy, esophagectomy, gastrectomy, liver/biliary resection, lung/bronchus resection, pancreatectomy, proctectomy, prostatectomy, or hysterectomy) from January 1 through September 30, 2016, for a corresponding cancer diagnosis. Readmission with a primary diagnosis of VTE. Proportion of 30-, 90-, and 180-day VTE readmissions after complex cancer surgery, factors associated with readmissions, and outcomes observed during readmission visit, including mortality, length of stay, hospital cost, and readmission to index vs nonindex hospital. For the 126 104 patients included in the study, 30-, 90-, and 180-day VTE-associated readmission rates were 0.6% (767 patients), 1.1% (1331 patients), and 1.7% (1449 of 83 337 patients), respectively. A majority of patients were men (58.7%), and the mean age was 65 years (SD, 11.5 years). For the 1331 patients readmitted for VTE within 90 days, 456 initial readmissions (34.3%) were to a different hospital than the index surgery hospital, median length of stay was 5 days (IQR, 3-7 days), median cost was $8102 (IQR, $5311-$10 982), and 122 patients died (9.2%). Independent factors associated with readmission included type of operation, scores for severity and risk of mortality, age of 75 to 84 years (odds ratio [OR], 1.30; 95% CI, 1.02-1.78), female sex (OR, 1.23; 95% CI, 1.11-1.37), nonelective index admission (OR, 1.31; 95% CI, 1.03-1.68), higher number of comorbidities (OR, 1.30; 95% CI, 1.06-1.60), and experiencing a major postoperative complication during the index admission (OR, 2.08; 95% CI, 1.85-2.33). In this cohort study, VTE-related readmissions after complex cancer surgery continued to increase well beyond 30 days after surgery. Quality improvement efforts to decrease the burden of VTE in postoperative patients should measure and account for these late VTE-related readmissions.


Comparing Techniques for Removing Fiber Endodontic Posts: A Systematic Review.
This systematic review aimed to establish the available techniques for fiber post removal, pointing out where each method stands out evaluating its advantages, and where they fall short indicating the possible harmful effects. This systematic review was registered in PROSPERO (CRD42020193799). A broad search of the electronic databases PubMed, Web of Science, Scopus, and Virtual Health Library was carried out before April 27, 2020, for in vitro studies about techniques for removing fiber posts luted with resin cements of endodontically treated teeth. The methodological quality of included studies was evaluated based on the critical assessment tool for in vitro studies. Thirteen articles were selected and included after applying the inclusion and exclusion criteria. All included studies received an assessment of methodological quality between high and moderate. Most studies used ultrasonic inserts as a strategy to remove fiber posts, manufactured removal kits and drills were also widely used, only one study evaluated the removal capacity of the Er:YAG laser. Ultrasonic inserts seem to lead to a greater working time for removal of the fiber post, tend to generate significant volume changes in the root structure and increase the temperature on the root canal and clean the root canal walls further. Although the results tend to show greater agility in removing fiber posts with manufactured removal kits and the ultrasonic inserts seem to work better in removing fiber remains and luting agent, there is still no consensus in the literature as to which technique is the best. In some cases, clinicians may be faced with the need to remove fiber posts in order to regain access to the root canal due to the need for endodontic retreatment which directly implies the search for the most appropriate removal technique. How to cite this article: Purger LO, Tavares SJO, Martinez RLCH, et al. Comparing Techniques for Removing Fiber Endodontic Posts: A Systematic Review. J Contemp Dent Pract 2021;22(5):587-595.


Predicting long-term dynamics of soil salinity and sodicity on a global scale.
Knowledge of spatiotemporal distribution and likelihood of (re)occurrence of salt-affected soils is crucial to our understanding of land degradation and for planning effective remediation strategies in face of future climatic uncertainties. However, conventional methods used for tracking the variability of soil salinity/sodicity are extensively localized, making predictions on a global scale difficult. Here, we employ machine-learning techniques and a comprehensive set of climatic, topographic, soil, and remote sensing data to develop models capable of making predictions of soil salinity (expressed as electrical conductivity of saturated soil extract) and sodicity (measured as soil exchangeable sodium percentage) at different longitudes, latitudes, soil depths, and time periods. Using these predictive models, we provide a global-scale quantitative and gridded dataset characterizing different spatiotemporal facets of soil salinity and sodicity variability over the past four decades at a ∼1-km resolution. Analysis of this dataset reveals that a soil area of 11.73 Mkm2 located in nonfrigid zones has been salt-affected with a frequency of reoccurrence in at least three-fourths of the years between 1980 and 2018, with 0.16 Mkm2 of this area being croplands. Although the net changes in soil salinity/sodicity and the total area of salt-affected soils have been geographically highly variable, the continents with the highest salt-affected areas are Asia (particularly China, Kazakhstan, and Iran), Africa, and Australia. The proposed method can also be applied for quantifying the spatiotemporal variability of other dynamic soil properties, such as soil nutrients, organic carbon content, and pH.


Multi-dimensional observation of white-light filaments generated by femtosecond laser pulses in condensed medium.
The generation dynamics of white-light filaments in a transparent condensed medium is investigated experimentally in both spatiotemporal and frequency domains. We visualize the creation of multiple refocusing filaments with gradual increase of laser power by characterizing their spatial distributions of plasma luminescence and corresponding far-field emission patterns. The spatial fusion of multiple refocusing filaments into a single relatively long plasma channel is found to take place at higher laser powers. The measurement of supercontinua indicates that filamentation of ultrashort laser pulses in dispersive bulk media is closely connected with subsequent temporal events of pulse single splitting, then multiple splittings and finally coalescence. In addition, typical interference patterns of far-field emission are observed in the experiment, which reveals the spatial coherent properties among transverse filaments that are produced by a single laser beam.


Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity.
Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator's innate function, with the inherent risk of pathogenic repeat expansions.


Salt intake, blood pressure, and socioeconomic disparities among government employees in Sri Lanka: a cross-sectional study.
Our study estimated salt intake, examined the association between blood pressure (BP) and salt intake, and explored the socioeconomic variations in salt intake among administrators (government employees). This is a cross-sectional study. We studied 168 randomly selected administrators aged 30-60 years attached to government offices in Colombo, Sri Lanka. Self-administered questionnaire gathered information on socio-demographic, work-related information, lifestyle practices, and medical history. BP, 24-hour urine collection, and anthropometric indices were measured. Mean salt intake levels measured by 24-hour Sodium (Na) excretion in hypertensives and non-hypertensives were 202.56 (SD ± 85.45) mmol/day and 176.79 (SD ± 82.02) mmol/day, respectively. A 100-mmol increase in sodium was associated with an average increase of 3.1 (95 per cent CI 2-4.2) mmHg in systolic BP and 1.8 (95 per cent CI 0.89-2.6) mmHg in diastolic BP. Higher salt intake was found in managerial assistants (12.38 ± 5.0 g) compared with senior officers (10.84 ± 4.9 g). Salt intake among these administrators was alarmingly high. High salt intake was positively associated with hypertension and more prevalent in lower socioeconomic strata.


Free Brick1 is a trimeric precursor in the assembly of a functional wave complex.
The Wave complex activates the Arp2/3 complex, inducing actin polymerization in lamellipodia and membrane ruffles. The Wave complex is composed of five subunits, the smallest of which, Brick1/Hspc300 (Brk1), is the least characterized. We previously reported that, unlike the other subunits, Brk1 also exists as a free form. Here we report that this free form of Brk1 is composed of homotrimers. Using a novel assay in which purified free Brk1 is electroporated into HeLa cells, we were able to follow its biochemical fate in cells and to show that free Brk1 becomes incorporated into the Wave complex. Importantly, incorporation of free Brk1 into the Wave complex was blocked upon inhibition of protein synthesis and incorporated Brk1 was found to associate preferentially with neosynthesized subunits. Brk1 depleted HeLa cells were found to bleb, as were Nap1, Wave2 or ARPC2 depleted cells, suggesting that this blebbing phenotype of Brk1 depleted cells is due to an impairment of the Wave complex function rather than a specific function of free Brk1. Blebs of Brk1 depleted cells were emitted at sites where lamellipodia and membrane ruffles were normally emitted. In Brk1 depleted cells, the electroporation of free Brk1 was sufficient to restore Wave complex assembly and to rescue the blebbing phenotype. Together these results establish that the free form of Brk1 is an essential precursor in the assembly of a functional Wave complex.


Semantic-enhanced Graph Contrastive Learning with Adaptive Denoising for Drug Repositioning.
The traditional drug development process requires a significant investment in workforce and financial resources. Drug repositioning as an efficient alternative has attracted much attention during the last few years. Despite the wide application and success of the method, there are still many shortcomings in the existing model. For example, sparse datasets will seriously affect the existing methods' performance. Additionally, these methods do not pay attention to the noise in datasets. In response to the above defects, we propose a semantic-enriched augmented graph contrastive learning with an adaptive denoising method, called SGCD. This method enhances data from the perspective of the embedding layer, deeply mines potential neighborhood relation-ships in semantic space, and combines similar drugs in the semantic neighborhoods into prototype comparison targets, thus effectively mitigating the impact of data sparsity on the model. Moreover, to enhance the model's robustness to noisy data, we use the adaptive denoising method, which can effectively identify noisy data in the training process. Exhaustive experiments on multiple real datasets show the effectiveness of the proposed model. The code implementation is available at https://github.com/yuhuimin11/SGCD-master.


Antithrombin III improved neutrophil extracellular traps in lung after the onset of endotoxemia.
Coagulation and inflammation are closely linked during acute inflammatory conditions, such as sepsis. Antithrombin (AT) is an anticoagulant that also has anti-inflammatory activities. The effects of therapeutically administering AT III after the onset of endotoxemia or sepsis were not clear. Here, we studied the effects of administering AT III after inducing lethal endotoxemia in mice. Mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxemia. AT III was administered 3 h later. We assessed survival and the severity of endotoxemia and quantified plasma cytokine levels and biochemical markers of liver and kidney function. In the lungs, we examined neutrophil accumulation, neutrophil extracellular traps, alveolar wall thickness, and chemokine (C-X-C motif) ligand 1 (cxcl-1), cxcl-2, and high mobility group box 1 expression. Administering AT III reduced the severity and mortality of LPS-induced endotoxemia as indicated by 24-h survival of 84% of the mice that received LPS + AT III and only 53% of mice given LPS alone (P < 0.05). AT III treatment attenuated several changes induced in the lungs by endotoxemia including cxcl-2 mRNA expression, high mobility group box 1 protein expression, neutrophil accumulation, alveolar septal thickening, and neutrophil extracellular trap formation. AT III did not decrease plasma cytokine levels or plasma urea nitrogen levels that were upregulated as a result of LPS-induced endotoxemia. Administration of AT III after the onset of endotoxemia improved outcomes in a mouse model. The attenuation of lung inflammation may have a large impact on mortality and morbidity. Because lung inflammation increases the likelihood of mortality from sepsis, AT III could be a useful agent in septic patients.


Dried plasma: state of the science and recent developments.
The early transfusion of plasma is important to ensure optimal survival of patients with traumatic hemorrhage. In military and remote or austere civilian settings, it may be impossible to move patients to hospital facilities within the first few hours of injury. A dried plasma product with reduced logistical requirements is needed to enable plasma transfusion where medically needed, instead of only where freezers and other equipment are available. First developed in the 1930s, pooled lyophilized plasma was widely used by British and American forces in WWII and the Korean War. Historical dried plasma products solved the logistical problem but were abandoned because of disease transmission. Modern methods to improve blood safety have made it possible to produce safe and effective dried plasma. Dried plasma products are available in France, Germany, South Africa, and a limited number of other countries. However, no product is available in the US. Promising products are in development that employ different methods of drying, pathogen reduction, pooling, packaging, and other approaches. Although challenges exist, the in vitro and in vivo data suggest that these products have great potential to be safe and effective. The history, state of the science, and recent developments in dried plasma are reviewed.


Anaesthetic management of abdominal hysterectomy in patient with congenital sinus node dysfunction.
A 45 years old woman having dysfunctional uterine bleeding was scheduled for total abdominal hysterectomy with bilateral salpingo-oophorectomy under general anaesthesia. On pre-operative anaesthesia assessment, she was found to have junctional rhythm at rate of 44 beats/minute with bigeminies and pre-mature ventricular contractions on ECG. On further evaluation, she was diagnosed as having congenital sinus node dysfunction on the basis of 24 hours Holter monitoring. She was asymptomatic, no prior comorbidity and belonged to functional class one. General anaesthesia was successfully managed by vigilance, invasive monitoring, standby transcutaneous and transvenous pacemakers; use of cardiostable and vagolytic anaesthetic agents like Etomidate, Atracurium and Pethidine during the procedure and for postoperative pain management. Transcutaneous external pacing pads were placed just after induction of anaesthesia, their functional apability was confirmed and was ready for use if needed. The transcutaneous and transvenous pacemakers were on backup and both were not required. Patient was successfully managed and was discharged home on third postoperative day with uneventful hospital course. The elective pacemaker implantation was therefore not required.


No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease.
Gluten ingestion leads to symptoms and small intestinal mucosal injury in patients with celiac disease. The only option is the strict lifelong exclusion of dietary gluten, which is difficult to accomplish. Many patients following a gluten-free diet continue to have symptoms and have small intestinal mucosal injury. Nondietary therapies are needed. We performed a phase 2 study of the ability of latiglutenase, an orally administered mixture of 2 recombinant gluten-targeting proteases, to reduce mucosal morphometric measures in biopsy specimens from patients with celiac disease. We performed a double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of latiglutenase in 494 patients with celiac disease (with moderate or severe symptoms) in North America and Europe, from August 2013 until December 2014. Participants reported following a gluten-free diet for at least 1 year before the study began. Patients with documented moderate or severe symptoms and villous atrophy (villous height:crypt depth ratio of ≤2.0) were assigned randomly to groups given placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. Subjects completed the Celiac Disease Symptom Diary each day for 28 days and underwent an upper gastrointestinal endoscopy with duodenal biopsy of the distal duodenum at baseline and at weeks 12 and 24. The primary end point was a change in the villous height:crypt depth ratio. Secondary end points included numbers of intraepithelial lymphocytes, serology test results (for levels of antibodies against tissue transglutaminase-2 and deamidated gliadin peptide), symptom frequencies, and safety. In a modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease. All groups had significant improvements in histologic and symptom scores. In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.


Anticholinergic Drug Burden in Noncancer Versus Cancer Patients Near the End of Life.
Anticholinergic drugs can cause several side effects, impairing cognition and quality of life (QOL). Cancer patients are often exposed to increasing cumulative anticholinergic load (ACL) as they approach death, but this burden has not been examined in patients with nonmalignant diseases. To determine ACL and its impact in noncancer versus cancer palliative care patients. We performed a secondary analysis of 244 subjects enrolled in a randomized controlled trial. ACL was quantified with the Anticholinergic Drug Scale. We used multivariable regression to calculate the effect of ACL on key outcomes, including drowsiness, fatigue, and QOL. Patients were stratified by diagnosis, and drugs were grouped as symptom management (SM) or disease management (DM). Overall, ACL in cancer and noncancer patients was not significantly different (2.6 vs. 2.4; P = 0.23). SM drugs caused greater anticholinergic exposure than DM drugs in both cancer and noncancer patients (2.3 vs. 0.5, and 1.5 vs. 1.3, respectively; both P < 0.05); however, DM drugs exposed noncancer patients to relatively more ACL than cancer patients (1.2 vs. 0.6, P < 0.0001). ACL was associated with worse fatigue (odds ratio, 1.08; CI, 1.002-1.17) and worse QOL (odds ratio, 0.89; CI, 0.80-0.98). ACL is associated with worse fatigue and QOL and may not differ significantly between cancer and noncancer patients nearing end of life. SM drugs are more responsible for ACL in cancer and noncancer patients, although DM drugs contribute significantly to ACL in the latter group. We recommend more attention to reducing anticholinergic use in all patients with life-limiting illness.


Habitat composition and connectivity predicts bat presence and activity at foraging sites in a large UK conurbation.
Urbanization is characterized by high levels of sealed land-cover, and small, geometrically complex, fragmented land-use patches. The extent and density of urbanized land-use is increasing, with implications for habitat quality, connectivity and city ecology. Little is known about densification thresholds for urban ecosystem function, and the response of mammals, nocturnal and cryptic taxa are poorly studied in this respect. Bats (Chiroptera) are sensitive to changing urban form at a species, guild and community level, so are ideal model organisms for analyses of this nature. We surveyed bats around urban ponds in the West Midlands conurbation, United Kingdom (UK). Sites were stratified between five urban land classes, representing a gradient of built land-cover at the 1 km(2) scale. Models for bat presence and activity were developed using land-cover and land-use data from multiple radii around each pond. Structural connectivity of tree networks was used as an indicator of the functional connectivity between habitats. All species were sensitive to measures of urban density. Some were also sensitive to landscape composition and structural connectivity at different spatial scales. These results represent new findings for an urban area. The activity of Pipistrellus pipistrellus (Schreber 1774) exhibited a non-linear relationship with the area of built land-cover, being much reduced beyond the threshold of ∼60% built surface. The presence of tree networks appears to mitigate the negative effects of urbanization for this species. Our results suggest that increasing urban density negatively impacts the study species. This has implications for infill development policy, built density targets and the compact city debate. Bats were also sensitive to the composition and structure of the urban form at a range of spatial scales, with implications for land-use planning and management. Protecting and establishing tree networks may improve the resilience of some bat populations to urban densification.


Beneficial Microorganisms for Corals (BMC): Proposed Mechanisms for Coral Health and Resilience.
The symbiotic association between the coral animal and its endosymbiotic dinoflagellate partner Symbiodinium is central to the success of corals. However, an array of other microorganisms associated with coral (i.e., Bacteria, Archaea, Fungi, and viruses) have a complex and intricate role in maintaining homeostasis between corals and Symbiodinium. Corals are sensitive to shifts in the surrounding environmental conditions. One of the most widely reported responses of coral to stressful environmental conditions is bleaching. During this event, corals expel Symbiodinium cells from their gastrodermal tissues upon experiencing extended seawater temperatures above their thermal threshold. An array of other environmental stressors can also destabilize the coral microbiome, resulting in compromised health of the host, which may include disease and mortality in the worst scenario. However, the exact mechanisms by which the coral microbiome supports coral health and increases resilience are poorly understood. Earlier studies of coral microbiology proposed a coral probiotic hypothesis, wherein a dynamic relationship exists between corals and their symbiotic microorganisms, selecting for the coral holobiont that is best suited for the prevailing environmental conditions. Here, we discuss the microbial-host relationships within the coral holobiont, along with their potential roles in maintaining coral health. We propose the term BMC (Beneficial Microorganisms for Corals) to define (specific) symbionts that promote coral health. This term and concept are analogous to the term Plant Growth Promoting Rhizosphere (PGPR), which has been widely explored and manipulated in the agricultural industry for microorganisms that inhabit the rhizosphere and directly or indirectly promote plant growth and development through the production of regulatory signals, antibiotics and nutrients. Additionally, we propose and discuss the potential mechanisms of the effects of BMC on corals, suggesting strategies for the use of this knowledge to manipulate the microbiome, reversing dysbiosis to restore and protect coral reefs. This may include developing and using BMC consortia as environmental "probiotics" to improve coral resistance after bleaching events and/or the use of BMC with other strategies such as human-assisted acclimation/adaption to shifting environmental conditions.


A hierarchical modeling approach to estimate regional acute health effects of particulate matter sources.
Exposure to particulate matter (PM) air pollution has been associated with a range of adverse health outcomes, including cardiovascular disease hospitalizations and other clinical parameters. Determining which sources of PM, such as traffic or industry, are most associated with adverse health outcomes could help guide future recommendations aimed at reducing harmful pollution exposure for susceptible individuals. Information obtained from multisite studies, which is generally more precise than information from a single location, is critical to understanding how PM impacts health and to informing local strategies for reducing individual-level PM exposure. However, few methods exist to perform multisite studies of PM sources, which are not generally directly observed, and adverse health outcomes. We developed SHared Across a REgion (SHARE), a hierarchical modeling approach that facilitates reproducible, multisite epidemiologic studies of PM sources. SHARE is a two-stage approach that first summarizes information about PM sources across multiple sites. Then, this information is used to determine how community-level (i.e., county-level or city-level) health effects of PM sources should be pooled to estimate regional-level health effects. SHARE is a type of population value decomposition that aims to separate out regional-level features from site-level data. Unlike previous approaches for multisite epidemiologic studies of PM sources, the SHARE approach allows the specific PM sources identified to vary by site. Using data from 2000 to 2010 for 63 northeastern US counties, we estimated regional-level health effects associated with short-term exposure to major types of PM sources. We found that PM from secondary sulfate, traffic, and metals sources was most associated with cardiovascular disease hospitalizations. Copyright © 2017 John Wiley & Sons, Ltd.


Rhesus monkey lens as an in vitro model for studying oxidative stress.
Lenses from young rhesus monkeys were incubated in the presence of H2O2 or oxygen radical generating systems to determine their suitability as a model for investigating lenticular oxidative stress. Additionally, direct comparisons were made between the effects found with the monkey lenses and those observed with cultured rat lenses exposed to the same oxidizing systems. As in earlier studies with rat lenses the monkey lenses exhibited impaired ability to actively accumulate from the medium radioactively labelled rubidium and choline following exposure to oxidative stress. Based on the effects of various scavengers of oxygen radicals it appeared that the mechanisms responsible for lens damage were the same for both rat and monkey lenses. However, rat lenses were damaged by lower concentrations of oxidants than were monkey lenses. It was concluded that oxidative stress affects both rat and monkey lenses by similar mechanisms but that lenses from monkeys, and probably other primates, are more resistant to these effects because they have better endogenous antioxidant defenses.


Tropical fruit camu-camu (Myrciaria dubia) has anti-oxidative and anti-inflammatory properties.
Oxidative stress as well as inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Although, various anti-oxidative dietary supplements have been evaluated for their ability to prevent atherosclerosis, no effective ones have been determined at present. "Camu-camu" (Myrciaria dubia) is an Amazonian fruit that offers high vitamin C content. However, its anti-oxidative property has not been evaluated in vivo in humans. To assess the anti-oxidative and anti-inflammatory properties of camu-camu in humans, 20 male smoking volunteers, considered to have an accelerated oxidative stress state, were recruited and randomly assigned to take daily 70 ml of 100% camu-camu juice, corresponding to 1050 mg of vitamin C (camu-camu group; n=10) or 1050 mg of vitamin C tablets (vitamin C group; n=10) for 7 days. After 7 days, oxidative stress markers such as the levels of urinary 8-hydroxy-deoxyguanosine (P<0.05) and total reactive oxygen species (P<0.01) and inflammatory markers such as serum levels of high sensitivity C reactive protein (P<0.05), interleukin (IL)-6 (P<0.05), and IL-8 (P<0.01) decreased significantly in the camu-camu group, while there was no change in the vitamin C group. Our results suggest that camu-camu juice may have powerful anti-oxidative and anti-inflammatory properties, compared to vitamin C tablets containing equivalent vitamin C content. These effects may be due to the existence of unknown anti-oxidant substances besides vitamin C or unknown substances modulating in vivo vitamin C kinetics in camu-camu.


Patient preferences for treatment: report from a randomised comparison of treatment strategies in early rheumatoid arthritis (BeSt trial).
To determine treatment preferences among patients with recent onset rheumatoid arthritis participating in a randomised controlled trial comparing four therapeutic strategies. A questionnaire was sent to all 508 participants of the BeSt trial, treated for an average of 2.2 years with either sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), or initial combination therapy with infliximab (group 4). Treatment adjustments were made every 3 months to achieve low disease activity (DAS < or =2.4). The questionnaire explored patients' preferences or dislikes for the initial therapy. In total, 440 patients (87%) completed the questionnaire. Despite virtually equal study outcomes at 2 years, more patients in group 4 reported much or very much improvement of general health: 50%, 56%, 46% and 74% in groups 1-4, respectively (overall, P<0.001). Almost half of the patients expressed no preference or aversion for a particular treatment group, 33% had hoped for assignment to group 4 and 38% had hoped against assignment to group 3. This negative perception was much less prominent in patients actually in group 3. Nevertheless, 50% of patients in group 3 disliked having to take prednisone, while only 8% in group 4 disliked going to the hospital for intravenous treatment. Within the limitations of our retrospective study, patients clearly preferred initial combination therapy with infliximab and disliked taking prednisone. After actual exposure, this preference remained, but the perception of prednisone improved. Patient perceptions need to be addressed when administering treatment.


Preparation and in Vitro Analysis of Human Serum Albumin Nanoparticles Loaded with Anthracycline Derivatives.
Nanoparticles prepared using human serum albumin (HSA) have emerged as versatile carriers for improving the pharmacokinetic profile of drugs. The desolvation of HSA using ethanol followed by stabilization through crosslinking with glutaraldehyde is a common technique for preparing HSA nanoparticles, but our knowledge concerning the characteristics (or functions) of HSA nanoparticles and their efficiency when loaded with drugs is limited. To address this issue in more detail, we prepared anthracycline-loaded HSA nanoparticles. Doxorubicin-loaded HSA nanoparticles with a size similar to doxorubicin-unloaded particles could be prepared by desolvating at a higher pH (8-9), and the size (100-150 nm) was optimum for delivery to tumor tissues. Using this procedure, HSA nanoparticles were loaded with other anthracycline derivatives, and all showed cytotoxicity in cancer cells. However, the efficiency of drug loading and dissolution rate were different among them possibly due to the differences in the type of association of the drugs on nanoparticles (doxorubicin and daunorubicin; covalently bound to nanoparticles, pirarubicin; both covalently bound to and adsorbed on nanoparticles, aclarubicin; adsorbed on nanoparticles). Since the formulation of such drug-loaded HSA nanoparticles should be modified for efficient delivery to tumors, the findings reported herein provide the useful information for optimizing the formulation and the production process for the HSA nanoparticles using a desolvation technique.


Dietary supplementation with probiotics during late pregnancy: outcome on vaginal microbiota and cytokine secretion.
The vaginal microbiota of healthy women consists of a wide variety of anaerobic and aerobic bacterial genera and species dominated by the genus Lactobacillus. The activity of lactobacilli helps to maintain the natural healthy balance of the vaginal microbiota. This role is particularly important during pregnancy because vaginal dismicrobism is one of the most important mechanisms for preterm birth and perinatal complications. In the present study, we characterized the impact of a dietary supplementation with the probiotic VSL#3, a mixture of Lactobacillus, Bifidobacterium and Streptococcus strains, on the vaginal microbiota and immunological profiles of healthy women during late pregnancy. An association between the oral intake of the probiotic VSL#3 and changes in the composition of the vaginal microbiota of pregnant women was revealed by PCR-DGGE population profiling. Despite no significant changes were found in the amounts of the principal vaginal bacterial populations in women administered with VSL#3, qPCR results suggested a potential role of the probiotic product in counteracting the decrease of Bifidobacterium and the increase of Atopobium, that occurred in control women during late pregnancy. The modulation of the vaginal microbiota was associated with significant changes in some vaginal cytokines. In particular, the decrease of the anti-inflammatory cytokines IL-4 and IL-10 was observed only in control women but not in women supplemented with VSL#3. In addition, the probiotic consumption induced the decrease of the pro-inflammatory chemokine Eotaxin, suggesting a potential anti-inflammatory effect on the vaginal immunity. Dietary supplementation with the probiotic VSL#3 during the last trimester of pregnancy was associated to a modulation of the vaginal microbiota and cytokine secretion, with potential implications in preventing preterm birth. ClinicalTrials.gov NCT01367470.


Proximal colon cancer and serrated adenomas - hunting the missing 10%.
There is a 10% shortfall in the number of proximal colorectal cancer cases detected by the UK Bowel Cancer Screening Programme and the actual number of UK-registered proximal colorectal cancers. Sessile serrated adenomas/polyps (SSA/P) are common premalignant lesions in the proximal colon and are notoriously difficult to spot endoscopically. Missed or dismissed SSA/Ps might contribute to this UK proximal colon cancer detection disparity. In Oxfordshire, a service evaluation audit and histological review has shown a linear increase in the detection rate of these lesions over the past 4 years. This is the result of increased endoscopist and pathologist awareness of these lesions and improved interdisciplinary communication. This is the result of increased endoscopist and pathologist awareness of these lesions, together with improved interdisciplinary communication, and we predict that this will lead to a comparable detection increase nationwide. Ongoing surveillance of an increasing number of these premalignant lesions could become a significant endoscopic resource requirement once UK guidelines on serrated lesion follow up are established.


Changes in Prices After an Excise Tax to Sweetened Sugar Beverages Was Implemented in Mexico: Evidence from Urban Areas.
In 2014 an excise tax to non-alcoholic sweetened beverages (SSB) was implemented in Mexico. The objective of this paper is to study whether and to what degree these taxes passed-through onto SSB prices in urban areas overall and by region, type of beverage and package size. Prices were obtained from the National Institute of Statistics and Geography from 2011 to 2014. We applied a pre-post quasi-experimental approach using fixed effects models. In sensitivity analysis we applied other model specifications to test the robustness of the findings and we also present weighted estimations based on household purchases. The dependent variables are real prices of a specific beverage category; the main independent variables are dummies for each month of 2014, and the models adjust for time trends and seasonality. Results suggest that the SSB tax passed along to consumers for all SSBs and we found overshifting for the carbonated SSBs. A greater effect is seen among the small package sizes, and we see heterogeneous effects by region. Estimating the effect of the tax on prices is important to understand the potential effect on consumption.


Youth Risk Behavior Surveillance - United States, 2017.
Health-risk behaviors contribute to the leading causes of morbidity and mortality among youth and adults in the United States. In addition, significant health disparities exist among demographic subgroups of youth defined by sex, race/ethnicity, and grade in school and between sexual minority and nonsexual minority youth. Population-based data on the most important health-related behaviors at the national, state, and local levels can be used to help monitor the effectiveness of public health interventions designed to protect and promote the health of youth at the national, state, and local levels. September 2016-December 2017. The Youth Risk Behavior Surveillance System (YRBSS) monitors six categories of priority health-related behaviors among youth and young adults: 1) behaviors that contribute to unintentional injuries and violence; 2) tobacco use; 3) alcohol and other drug use; 4) sexual behaviors related to unintended pregnancy and sexually transmitted infections (STIs), including human immunodeficiency virus (HIV) infection; 5) unhealthy dietary behaviors; and 6) physical inactivity. In addition, YRBSS monitors the prevalence of other health-related behaviors, obesity, and asthma. YRBSS includes a national school-based Youth Risk Behavior Survey (YRBS) conducted by CDC and state and large urban school district school-based YRBSs conducted by state and local education and health agencies. Starting with the 2015 YRBSS cycle, a question to ascertain sexual identity and a question to ascertain sex of sexual contacts were added to the national YRBS questionnaire and to the standard YRBS questionnaire used by the states and large urban school districts as a starting point for their questionnaires. This report summarizes results from the 2017 national YRBS for 121 health-related behaviors and for obesity, overweight, and asthma by demographic subgroups defined by sex, race/ethnicity, and grade in school and by sexual minority status; updates the numbers of sexual minority students nationwide; and describes overall trends in health-related behaviors during 1991-2017. This reports also summarizes results from 39 state and 21 large urban school district surveys with weighted data for the 2017 YRBSS cycle by sex and sexual minority status (where available). Results from the 2017 national YRBS indicated that many high school students are engaged in health-risk behaviors associated with the leading causes of death among persons aged 10-24 years in the United States. During the 30 days before the survey, 39.2% of high school students nationwide (among the 62.8% who drove a car or other vehicle during the 30 days before the survey) had texted or e-mailed while driving, 29.8% reported current alcohol use, and 19.8% reported current marijuana use. In addition, 14.0% of students had taken prescription pain medicine without a doctor's prescription or differently than how a doctor told them to use it one or more times during their life. During the 12 months before the survey, 19.0% had been bullied on school property and 7.4% had attempted suicide. Many high school students are engaged in sexual risk behaviors that relate to unintended pregnancies and STIs, including HIV infection. Nationwide, 39.5% of students had ever had sexual intercourse and 9.7% had had sexual intercourse with four or more persons during their life. Among currently sexually active students, 53.8% reported that either they or their partner had used a condom during their last sexual intercourse. Results from the 2017 national YRBS also indicated many high school students are engaged in behaviors associated with chronic diseases, such as cardiovascular disease, cancer, and diabetes. Nationwide, 8.8% of high school students had smoked cigarettes and 13.2% had used an electronic vapor product on at least 1 day during the 30 days before the survey. Forty-three percent played video or computer games or used a computer for 3 or more hours per day on an average school day for something that was not school work and 15.4% had not been physically active for a total of at least 60 minutes on at least 1 day during the 7 days before the survey. Further, 14.8% had obesity and 15.6% were overweight. The prevalence of most health-related behaviors varies by sex, race/ethnicity, and, particularly, sexual identity and sex of sexual contacts. Specifically, the prevalence of many health-risk behaviors is significantly higher among sexual minority students compared with nonsexual minority students. Nonetheless, analysis of long-term temporal trends indicates that the overall prevalence of most health-risk behaviors has moved in the desired direction. Most high school students cope with the transition from childhood through adolescence to adulthood successfully and become healthy and productive adults. However, this report documents that some subgroups of students defined by sex, race/ethnicity, grade in school, and especially sexual minority status have a higher prevalence of many health-risk behaviors that might place them at risk for unnecessary or premature mortality, morbidity, and social problems (e.g., academic failure, poverty, and crime). YRBSS data are used widely to compare the prevalence of health-related behaviors among subpopulations of students; assess trends in health-related behaviors over time; monitor progress toward achieving 21 national health objectives; provide comparable state and large urban school district data; and take public health actions to decrease health-risk behaviors and improve health outcomes among youth. Using this and other reports based on scientifically sound data is important for raising awareness about the prevalence of health-related behaviors among students in grades 9-12, especially sexual minority students, among decision makers, the public, and a wide variety of agencies and organizations that work with youth. These agencies and organizations, including schools and youth-friendly health care providers, can help facilitate access to critically important education, health care, and high-impact, evidence-based interventions.


Clinical competence in internal medicine.
To describe more explicitly the components of competence required of the internist, The American Board of Internal Medicine has analyzed the medical encounter and defined the major variables involved: the abilities required of the internist, the tasks that must be performed to solve a medical problem, the medical illness, and the patient. The abilities of the internist have been categorized into attitudes and habits, interpersonal skills, motor and technical skills, and intellectual abilities. The latter have been further subdivided into the abilities to acquire and use knowledge, to organize, to synthesize information, and to apply clinical judgment. For each of these abilities statements of clinical competence that relate to the tasks required have been developed. The Board is publishing this paper, an excerpt of a longer document, with the hope that it will be useful to residents, faculty, and practicing internists.


Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay.
The NeoAzure study has demonstrated that the use of the bisphosphonate zoledronic acid (Zol) in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity. The purpose of this study was to compare the antitumor effect of Zol with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA). Breast cancer specimens were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Department of Obstetrics and Gynecology, Tübingen, Germany, between 2006 through 2009. Antitumor effects of Zol, TAC (Docetaxel, Adriamycin, Cyclophosphamide) and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50), for IC90 and for the sensitivity index (IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls. The median IndexSUM value was lower for Zol than for the combined regimen FEC (36.8%) and TAC (12.9%), respectively, indicating increased antitumor activity of Zol in primary breast cancer cells. The difference regarding Zol and FEC was significant (p < 0.05). The median IC50 value for Zol (8.03% TDC) was significantly lower than the IC50 values for FEC (33.5% TDC) and TAC (19.3% TDC) treatment (p < 0.05). However, the median IC90 value for Zol (152.5% TDC) was significantly higher than the IC90 value obtained with TAC (49.5% TDC; p < 0.05), but similar to the IC90 value for FEC (180.9% TDC). In addition a significant positive correlation was observed for the IndexSum of Zol and the ER status (p < 0.01). Zoledronic acid has a strong antitumor effect on primary breast cancer cells in vitro which is equal or superior to commonly used chemotherapeutic regimens for treating breast cancer.


Understanding multipeak phenomena in actively Q-switched fiber lasers.
Dynamics of split pulses in actively Q-switched fiber lasers are numerically investigated, and the mechanism that produces multipeak phenomena (MPP) is precisely illustrated. It is shown that the first transient pulse in a cavity is initiated by the quick switching of a Q-switching element, which actually injects part of the amplified spontaneous emission into the laser cavity in the form of a pulse. Then the multipeak structures are related to the evolution of the perturbation caused by the switching and are determined by the rise time of the switching and by conditions of photon density and population inversion.